The primary Na absorbing pathways in the mammalian small intestine are Na-glucose co-transport (SGLT-I) and coupled NaCI absorption. How constitutive nitric oxide (cNO), known to regulate many gastrointestinal tract functions, may regulate these important Na absorbing pathways in the normal mammalian small intestine is not well understood. Preliminary studies from our laboratory indicate that cNO uniquely regulates these two primary Na absorbing pathways in the small intestine in a complementary fashion to achieve cellular Na homeostasis. Our preliminary studies indicate that in physiological states cNO facilitates SGLT-1 by modulating its affinity for glucose whereas cNO represses NHE3 by modulating its transporter numbers. Given this background we hypothesize that cNO uniquely regulates primary Na absorbing pathways in the mammalian small intestine. Thus, the overall goal of this proposal is to determine the mechanism of regulation of Na absorption by nitric oxide in the normal mammalian small intestine. This study will shed novel insight into the active regulation of and decipher the mechanisms of modulation of essential Na absorbing transport processes by cNO in the normal intestine. It will also provide new insights into the cNO mediated intracellular regulation of these transport processes. Further, the results of these studies will set the stage to decipher the mechanism of regulation of these important Na absorptive pathways in inflammatory bowel disease (IBD). In IBD understanding the regulation of Na absorption is important since, it is known that morbidity of IBD stems from its effect on electrolytes, nutrients and fluid absorption; thus, patients with IBD sustain malabsorption and diarrhea with attendant malnutrition and weight loss. Better understanding of the mechanism of regulation of Na-absorbing transport processes by NO in the normal and chronically inflamed intestine will provide the basis for new and more efficacious treatment modalities for the malabsorption, diarrhea and malnutrition of IBD.